Method of inhibiting platelet activation

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai

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514 2, 514822, A61K 3702

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active

051964031

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BRIEF SUMMARY
TECHNICAL FIELD OF THE INVENTION

The present invention relates to polypeptide inhibitors of platelet activation and derivatives thereof, purified from the venom of the North American Water Moccasin and to methods for their purification. This invention also relates to DNA sequences and recombinant DNA molecules which code for these polypeptide inhibitors of platelet activation. And this invention relates to recombinant DNA molecules which code for fusion proteins comprising both a polypeptide inhibitor of platelet activation and a conventional anti-thrombin polypeptide. This invention also relates to pharmaceutically acceptable compositions and methods characterized by at least one of these natural or recombinant inhibitors of platelet activation, alone or in combination with conventional anti-thrombin compounds. The compositions, combinations and methods of this invention are particularly useful in the treatment of thrombotic diseases.


BACKGROUND ART

Platelet aggregation and release reactions (collectively known as platelet activation) are essential to hemostasis. However, perturbations in platelet mechanisms controlling hemostasis may yield thrombi (blood clots) which are pathogenic when blood flow to dependent tissues is occluded. This is the case in a variety of life-threatening vascular diseases, such as myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis, peripheral arterial occlusion and other blood system thromboses. Therefore, strategies to control platelet aggregation and release are desirable in the treatment of these diseases [L. A. Harker and M. Gent, "The Use of Agents that Modify Platelet Function in the Management of Thrombotic Disorders" in Hemostasis and Thrombosis, R. W. Colman et al., eds., pp. 1438-56, J. B. Lippincott, Co., Philadelpha, Pa. (1987)]. Furthermore, inhibition of platelet aggregation maya also be desirable in the case of extracorporeal treatment of blood, such as in dialysis, storage of platelets in platelet concentrates and following vascular surgery.
A large number of compounds, both naturally occurring and synthetic, are known to cause platelet aggregation and release. These include ADP, collagen, arachidonic acid, epinephrine, thrombin, ristocetin, and the thromboxane A.sub.2 mimetic, U46619. The mechanism by which each of these compounds causes platelet aggregation or release varies and involves one of several different receptors on the platelet surface.
A wide variety of antiplatelet agents are currently used for prophylaxis and treatment of arterial thrombotic disorders. Because most of these agents are specific for particular platelet aggregation and/or secretion mechanisms, the agent of choice in a given regimen depends upon the particular mode of platelet activation sought to be inhibited. Antiplatelet agents act in a wide variety of ways, including inhibition of platelet cyclooxygenase, antagonism of the thromboxane A.sub.2 receptor, inhibition of thromboxane A.sub.2 synthetase, elevation of cAMP levels, and antagonism and neutralization of platelet surface glycoprotein IIb/IIIa.
Glycoprotein IIb/IIIa is the platelet fibrinogen receptor. It self-associates as a two-chain complex in a calcium-dependent manner, upon stimulation of platelets with ADP, epinephrine, thrombin or prostaglandin derivatives and precursors thereof [S. J. Shattil et al., "Changes in the Platelet Membrane Glycoprotein IIb/IIIa Complex During Platelet Activation", J. Biol. Chem., 260, pp. 11107-14 (1985); G. A. Margeurie et al., "Human Platelets Possess an Inducible and Saturable Receptor Specific for Fibrinogen", J. Biol. Chem., 254, pp. 5357-63 (1979)]. This results in platelet aggregation mediated by a cross-linking between fibrinogen and the activated glycoprotein IIb/IIIa complexes of two platelets. Specifically, the glycoprotein IIb/IIIa binds to an Arg-Gly-Asp sequence in fibrinogen [M. D. Pierschbacher and E. Ruoslahti, "Cell Attachment Activity of Fibronectin Can be Duplicated By Small Synthetic Fragments of the Molecule", Nature, 309, pp. 30-33 (1984); K. M.

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